The full universe is full of pathogens which we need to contend off to go forth a normal life. Due to this, we have an immune system that helps us contend off and prevent/manage subsequent infections. Our immune system can be classified into two, the innate and acquired immune responses. The innate immune response is loosely specific and provides the first defensive action against any infection. Their response to any subsequent infection stays the same as the initial infection. In contrast, the acquired immune response is extremely specific such that it provides defense mechanism by bring forthing antibodies specific to an antigen. They besides have the capacity of maintaining infection memory such that there will be a more powerful response to future infections. Innate immune response is largely provided by macrophages, dendritic cells, polymorphonuclear leucocytes, mast cells, natural slayer cells, red blood cells and thrombocytes. The acquired immune response is provided by lymph cells, the T ( T cells ) and B lymph cells ( B cells ) .
The lymph cells are derived from haematopoietic root cells ( HSC ) in the bone marrow. That signifier MLPs ( myeloid-lymphoid primogenitors ) . If the HSC and MLP stay in the bone marrow they form B cells and if they migrate ( via blood ) to the Thymus they form T cells ( see figure below ) .
Initiation of immune response by the lymph cells first requires acknowledgment of the antigens and this is achieved by cell surface receptors called BCRs ( B cell receptor ) and TCRs ( T cell receptor ) . These two receptors have great similarities and differences in their construction composites, antigen acknowledgment, cell activation and familial recombination.
A ) STRUCTURE OF BCRs AND TCRs
Both the BCR and TCR have great similarities and differences in the construction. They both exist as multi-chain composites as seen in the diagrams below:
I ) Antigen acknowledgment constituents
In the figure above, subdivision A shows the construction of a BCR. The BCR antigen acknowledgment medium is an Ig ( Ig ) molecule ( a transmembrane antibody ) . The antibody is modified via alternate splice that adds a hydrophobic transmembrane sphere and a short cytoplasmic sphere ( ~3 aminoacids ) at the C end point of the immunoglobulin heavy concatenation ( Wall & A ; Kuehl 1983 ) . All naA?ve B cells merely show both IgM and IgD categories of Ig but do exchange to other categories upon activation by antigens ( Goding, 1978 ) . The antibody ( figure 2C ) is a extremely specific Ig that can follow any one of the 5 Ig isotopes, IgG, IgA, IgM, IgD and IgE. The antibody has 3 parts of which 2 parts ( FAB ) vary from antibody to antibody and bind to antigens and 1 part ( FC ) that binds to effector molecules. The antibody is composed of 2 visible radiation and 2 heavy ironss held together by inter and intra disulphide bonds. The heavy ironss depending on the Ig isotypes can be any one of I? , Aµ , I± , I? or E› ironss. The variable spheres ( VH and VL ) bind to antigen and besides conveying about variableness and antigen acknowledgment specificity. This specificity is chiefly due to the presence of 3 hypervariable parts ( Complementary Determining Regions ) , viz. CDR1, CDR2 and CDR3 in the variable parts.
Similar to BCR, the antigen acknowledgment medium in TCR is an immunoglobulin heterodimer made from I± and I? Ig ironss ( in most T cells ) or I? and I? Ig ironss. Unlike in BCRs where the IG can be of 5 types, in TCRs the Ig heterodimers are merely of 2 types. The two Ig ironss in TCRs are ( besides like BCRs ) held together by intra and inter disulphide bonds. As seen in subdivision C, each Ig concatenation creases into 2 spheres, the variable and the changeless sphere. This turn uping greatly resembles the FAB part of the antibody in BCRs. Likewise antibodies, the I±I? and I?I? heterodimers besides have hypervariable parts ( CDR1, CDR2 and CDR3 ) in variable spheres. The variable parts in both BCRs and TCRs bring about specificity and diverseness
The BCR antibodies have a flexible joint articulation ( linking FAB and FC ) that makes the Ig molecule really flexible. Unlike antibodies, the flexibleness of the TCR Ig molecule is really limited at the elbow part ( junction of changeless and variable part ) ( Degano et al, 1996 ) .
two ) ACCESSORY PROTEINS
Both the BCR and TCR have really short cytoplasmic spheres that restrict the binding of any signal transduction factors to the receptors. Due to this the receptors are unable to transducer signals into cells upon antigen acknowledgment. Signal transduction is achieved via the accessary proteins. BCRs ( figure 2 subdivision A ) accoutrement proteins consists of one or more dimmers of one each of Ig-I± and Ig-I? ironss held together in the cell membrane by a brace of disulphide bonds. The cytoplasmatic spheres of these ironss have phosphorylation sites called ITAMS. Unlike BCR accoutrement protein, the TCR accoutrement proteins ( figure 2, subdivision C ) is composed of a complex know as CD3. It consists of 3 types of invariant ironss, viz. I? , I? and E› . A I? or I? concatenation couples up with one E› concatenation ( by formation of disulphide bonds ) each to organize two dimmers ( I?E› and I?E› ) . In add-on to this, a dimmer of 2 zeta ( I¶ ) ironss is besides present. Together, these 3 dimers make up the CD3 composite. The I¶ ironss have a much longer cytoplasmatic tail than the I? , I? and E› ironss and have 3 ITAMs as compared to one in the I? , I? and E› ironss. Therefore for both BCR and TCR accoutrement proteins are dimmers that all contain ITAMs.
B ) GENERATION OF RECEPTOR DIVERSITY
There are 1000000s antigens and we need to bring forth 1000000s of antibodies against them. However, we do non hold 1000000s of Ig cistrons so how are we able to bring forth all these different antibodies? The reply is antibodies are produced in developing B cells via familial recombination of cistrons encoding the Igs ( Hozumi and Tonegawa, 1976 ) . The figure below shows the cistron sections coding Igs.
Figure fable: The human heavy concatenation locus as shown in the last row, consists of about 38-46 functional VH cistrons, 27 DH and 6 JH cistrons. The light concatenation can be either made of I» or I? ironss. The I» venue consists of about 30 functional V I» cistrons and 5 J I» cistrons each separated by a J sections. The Kappa venue has about 34-40 functional VI? cistrons and 5 JI? cistrons.
The variable heavy concatenation part of the antibody is made from the connection of the V ( variable ) , D ( diverseness ) and J ( articulation ) cistron sections and the variable visible radiation concatenation ( which can be either I? or I» ) is formed from the connection of V and J sections merely. A procedure called V ( D ) J recombination involves fall ining different cistron sections and as a consequence conveying about antibody diverseness. At the heavy concatenation venue, any one of the 27 D and 6 J cistron sections are foremost joined together and so any one of 46 V cistron section is joined to this DJ section. This rearranged Deoxyribonucleic acid is so transcribed to organize a primary messenger RNA. This messenger RNA so undergoes splicing to convey the VDJ section near to the changeless cistron section. Additional diverseness is achieved as any 1 of the two types of visible radiation ironss can be formed. Random interpolation of bases either side of D sections besides creates N-nucleotide diverseness. In entire about 106 possible Ig cistron combinations can be formed. This recombination procedure is driven by recombination signal sequences that flank the coding cistron sections. Certain enzymes ( RAG-1 and RAG-2 ) aid intercede this bodily recombination procedure. The antibodies produce undergo a procedure of clonal selectin where merely the antibody specific to the antigen preferentially proliferates to do many antibodies.
Adhering affinity of BCR is greatly increased after antigen acknowledgment where the variable parts of both heavy and light concatenation undergo bodily hypermutations. This is where point mutants are put in the variable parts of quickly proliferating B cells. These mutants produce antibodies that may hold good, moderate or good affinity for the antigens. The antibody with good affinity will hold a selective advantage during clonal choice.
The cistron segements encoding TCR I? concatenation follow the similar V, D, J and C agreement of BCRs. The recombination procedure involves of of the two DI? cistrons rearranges next to one of JI? cistrons. Then one of the ~50 V cistrons arranges following to the preformed DI?JI? cistrons. As seen, this is besides similar to the B cells where a DJ segement signifiers foremost and so joins up with a V section. There is besides random interpolation, merely like in B cells, of bases either side of D sections to make N-nucleotide diverseness. Unlike in B cells, there is no bodily hypermutation in T cells after antigen acknowledgment. If this occurs, the TCR will free its ability to recognize MHC and the peptide it presents.
C ) ANTIGEN BINDING/RECOGNITION
BCR and TCR have similar Ig antigen acknowledgment receptors but the types of antigens they recognise are really different. BCR can recognize naA?ve ( as a whole ) antigens and TCR can merely recognize a individual antigen peptide sequence presented onto cell surfaces by MHC ( Major histocompatibility composite ) molecules. The antigens recognised by B cells are naA?ve and hence the antibody in BCR largely recognise discontinuous antigenic determinants on the antigen and antigens recognised by the TCR is in signifier of additive peptide sequences and hence they largely recognise uninterrupted or additive antigenic determinants.
Antigen acknowledgment by BCR is really simple where the antibody variable part merely recognises specific antigenic determinants on antigen and bind to it. The BCR can recognize 3 types of antigens, Type 1 Thymus independent antigens ( where bacterial lipoproteins can adhere to mitogenic beltway molecules on B cells surface and this allows non-specific antigen B cell activation ) , Type 2 thymus independent antigens ( appiles to antigens that have good spaced and insistent polyoses that bind to multiple antibodies in BCR and trip the B cell ) and Thymus dependant antigens ( necessitate helper T cells ) . Thymus dependent antigens when bind to TCR, alternatively of doing activation usually do anergy. Due to this, one time the binding has occurred, the whole antigen+TCR comples is endocytosed, the antigen is hydrolysed by enzymes and processed to little additive peptides and so presented onto the B cell surface via MHC2 molecules. Helper T cells so recognize this peptide-MHC composite. B cells have tonss of CD40 on their surface that binds to CD40L nowadays on Th assistant cells. In response to this Th cells secrete IL-4, 5, 6 that besides help trip other costimulatory molecules in the BCR coreceptor composite. All these events provide costimulation of the B cells and it is activated.
I±I? heterodimer TCRs in comparing can recognize any type of antigen that is processed and presented as a individual peptide on MHC1 on mark cells and MHC2 on B cells, macrophages and dendritic cells ( all professional antigen showing cells ) . The non-covalent forces that help TCR bind to the peptide-MHC composite are similar to the forces that enable the antibody bond to the antigen i.e. noncovalent.
Unlike BCR that merely have to recognize antigenic determinants on antigens, the TCR has to both recognize the presence of both MHC molecule and antigen peptide. The TCR VI± ( variable alpha part ) overlays I±2 spiral of MHC1 or I?1 spiral of MHC2 and the VI? sphere sheathings I±1 spiral in both MHC1/2. The CDR1 and CDR2 bind to I± spirals of MHC and the CDR3 ( which is more variable ) , binds to the antigen peptide on MHC. This construct is summarised in the image below:
Figure fable: The image shows how the TCR variable complementarity finding parts ( CDR ) which are the binding sites interact with peptide-MHC composite. The CDR1 and CDR2 bind to the MHC alpha spirals and CFR3 binds to the peptide.
The I?I? TCRs are more similar to BCR antibody as they can recognize naA?ve antigens without the demand of processed antigen presentation. Another similarity of BCR and I?I? TCRs is that in the antibodies of BCRs, the CDR3 parts on heavy concatenation are shorter than the CDR3 in heavy ironss and besides the same in I?I? TCRs is seen where the I? are shorter than the I? CD3.
COSTIMULATIONS
Both lymph cells do non acquire activated ( but undergo anergy ) once they recognise and bind to an antigen. They require costimulatory signals that will finally take to the activation of the lymph cells. The B cells have BCR carbon monoxide receptor complex consisting of CD19 and CD21 ( complement receptor ) , CD81 and LEU13 ( interferon induced transmembrane protein 1 ) . All these molecules are stimulated in presence of interferons and complements that give a costimulatory signal to B cells and activate it when it has recognised an antigen. The precise inside informations of how these costimulatory molecules stimulate B cell signalling are still under probe.
In contrast to the 4 chief costimulatory molecules in B cells, the primary costimulatory molecule in T cells is CD28 ( figure besides )
The binding of peptide-MHC to TCR causes up-regulation of certain molecules ( e.g. CD28 ) . T cells, like B cells can be costimulated by either cytokines or costimulatory molecule interactions.
Armored personnel carriers have surface molecules such as the B7.1 and B7.2 ( or the CD80 and CD86 ) that recognise and bind to a molecule on the surface of the T cells called CD28 found on Cadmium. This interacting provides co stimulation. The CTLA4 molecule is extremely expressed after proliferation of the T cells. Once it binds to B7, alternatively of carbon monoxide exciting T cells, it turns the T cells “ off ” . This is helpful in forestalling inordinate immune responses. No such regulative mechanism is seen in B cells.
A alone characteristic of T cells is that they have co receptors ( CD4 and CD8 ) that help recognize the MHC molecules. CD4 molecules act as co receptors for MHC2 and are found on helper T cells and CD8 molecules present on cytotoxic T cells help recognize MHC1 molecules.
ACTIVATION OF B AND T CELLS
The activation of B and T cells following antigen acknowledgment is someway similar as it involves the phosphorylation of the ITAMS of accessary proteins. In B cells, antigen binding and carbon monoxide stimulation recruits the BCR+antigen to lipid tonss that brings protein tyrosine kinase Lyn stopping point to the ITAMs of the cytoplasmatic dress suits of the BCR associated proteins. Lyn phosphorylates ITAMs and triggers a signal cascade that consequences in addition of cytoplasmatic Ca degrees that activate written text factors that control the entry of B cells into cell rhythm. Finally activate the B cells which so form plasma cells ( that make tonss of ringers of antibodies to the antigen ) and memory cells that will assist pull off subsequent infections. The initial proliferation of the activated B cell is accompanied by bodily hypermutation of the rearranged antibody variable cistrons that lead to the production of antibodies that may hold hapless, moderate or good binding capacity to the antigen. The good binding antibodies will be preferentially selected during clonal choice and they will further undergo proliferation to bring forth plasma and memory cells.
A similar state of affairs besides occurs in T cells where there is activation of lipid tonss that bring the zeta concatenation ITAMS near to Lck ( a protein tyrosine kinase ) that phosphorylates the ITAMs and hence create chance for other factors to adhere to it and finally do mobilisation of Ca that causes proliferation of T cell into Helper T cells, Regulatory T cells and Cytotoxic T cells.
